Elucidation of the mechanism of resistance to apoptosis in ALK rearranged NSCLC

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15922
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kanazawa University
• Principal Investigator: Tanimoto Azusa 金沢大学, がん進展制御研究所, 助教 (90776444)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ALK / Mcl-1 / Noxa

Outline of Final Research Achievements

We used integrated clinical and next-generation sequencing data. ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs.In 90 ALK-rearranged NSCLC patients who were treated with a selective ALK-TKI, alectinib, TP53 co-mutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months vs.NR; p=0.0008; hazard ratio, 0.33]. ALK-rearranged NSCLC cell lines which lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazommib markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a pro-apoptotic protein, Noxa which bound to an anti-apoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with non-functional p53.

Free Research Field

肺癌

Academic Significance and Societal Importance of the Research Achievements

ALK融合遺伝子陽性肺癌の約1/4にTP53変異が共存しており、本来有効であるALK阻害薬の効果を減弱させる要因となっていることが明らかにした。TP53変異はEGFR遺伝子などの他のドライバー遺伝子変異陽性肺癌にも共存しており、本研究は選択的Mcl-1阻害薬の開発の意義が高めた。